期刊
PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY
卷 96, 期 1-3, 页码 421-451出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pbiomolbio.2007.07.010
关键词
late sodium current; heart failure; calcium; action potential; numerical model; sodium-calcium exchanger
资金
- Intramural NIH HHS Funding Source: Medline
- NHLBI NIH HHS [R01 HL074328-04, HL-53819, HL074238] Funding Source: Medline
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL053819, R01HL074328] Funding Source: NIH RePORTER
Most cardiac Na+ channels open transiently upon membrane depolarization and then are quickly inactivated. However, some channels remain active, carrying the so-called persistent or late Na+ current (I-NaL) throughout the action potential (AP) plateau. Experimental data and the results of numerical modeling accumulated over the past decade show the emerging importance of this late current component for the function of both normal and failing myocardium. I-NaL is produced by special gating modes of the cardiac-specific Na+ channel isoform. Heart failure (HF) slows channel gating and increases I-NaL, but HF-specific Na+ channel isoform underlying these changes has not been found. Na+ channels represent a multi-protein complex and its activity is determined not only by the pore-forming alpha subunit but also by its auxiliary beta subunits, cytoskeleton, calmodulin, regulatory kinases and phosphatases, and trafficking proteins. Disruption of the integrity of this protein complex may lead to alterations of I-NaL in pathological conditions. Increased I-NaL and the corresponding Na+ flux in failing myocardium contribute to abnormal repolarization and an increased cell Ca2+ load. Interventions designed to correct I-NaL rescue normal repolarization and improve Ca2+ handling and contractility of the failing cardiomyocytes. This review considers (1) quantitative integration of I-NaL into the established electrophysiological and Ca2+ regulatory mechanisms in normal and failing cardiomyocytes and (2) a new therapeutic strategy utilizing a selective inhibition of I-NaL to target both arrhythmias and impaired contractility in HF. (C) 2007 Elsevier Ltd. All rights reserved.
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